DETAILED ACTION
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.
Applicant's submission filed on 29 August 2025 has been entered, and the arguments presented therein have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claim Interpretation
Claim 1 recites a lipid nanoparticle comprising an outer lipid monolayer. For the purposes of examination under prior art, the examiner understands a vesicular lipid nanoparticle or a liposome having a bilayer to be within the claim scope. Said bilayer in a liposome would have comprised an inner layer of the bilayer and an outer layer of the bilayer. The examiner understands the “outer lipid monolayer” to refer to the outer layer of the bilayer. In support of this position, the examiner cites the last paragraph of page 13 of the specification as filed, which indicates that the composition may be a vesicle; the skilled artisan would have understood that a vesicle comprises an interior aqueous space and a lipid bilayer. With that being said, the claim is not understood to be limited to a nanostructure with an outer lipid bilayer and can include a nanostructure with an outer lipid monolayer; however, the skilled artisan would have expected such a structure to have had a lipidic interior rather than an aqueous interior.
Claim 1 recites an ion that is anionic, as well as a charged lipid that comprises anionic lipids. The examiner understands the claim to require that the ion is a different component as compared with the charged lipids. As such, a composition comprising an anionic lipid but lacking an additional anion is not understood to meet the claim limitations because it lacks the ion which is anionic.
Claim 1 recites neutral lipids. The examiner understands zwitterionic lipids having a positive charge and a negative charge to be neutral lipids. Phosphatidylcholine lipids are a well-known example of zwitterionic (and thereby neutral) lipids. The examiner also understands phosphatidylethanolamine lipids to be zwitterionic (and thereby neutral) lipids because phosphatidylethanolamine comprises an anionic phosphate group and an amine group that is protonated and positively charged at neutral pH. These two opposing charges cancel each other and render phosphatidylethanolamine to be neutral.
Claim 9 recites the phrase “normalized release.” This is defined as of the last paragraph of page 4 of the instant specification.
Claim Rejections - 35 USC § 103 – Obviousness
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 4-9, 12-17 and 37 is/are rejected under 35 U.S.C. 103 as being unpatentable over Szoka Jr. et al. (US Patent 5,077,057) in view of Barenholz (Journal of Controlled Release 160 (2012), page 117-134) and Hayes et al. (US 2017/0239182 A1).
Szoka Jr. et al. (hereafter referred to as Szoka) is drawn to liposomes, as of Szoka, title and abstract. Szoka teaches encapsulation of doxorubicin in anionic liposomes, as of Szoka, column 10, Example 2, reproduced in part below.
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The examiner understands that “EPG” refers to egg phosphatidylglycerol and is an anionic lipid. The examiner understands that “EPC” refers to egg phosphatidylcholine and is a neutral lipid which is zwitterionic. The examiner understands that “Chol” refers to cholesterol and is a neutral lipid. Doxorubicin reads on the required charged active agent; however, Szoka teaches other active agents elsewhere in the document such as cis-platinum (i.e. cisplatin) in Example 4.
Szoka fails to teach an ion that is a separate component from the anionic lipid.
Barenholz is drawn to a doxorubicin containing liposome known as “Doxil” as of Barenholz, page 117, title and abstract. The doxorubicin liposome of Barenholz was loaded with an ammonium sulfate gradient, as of Barenholz, abstract. As best understood by the examiner, this would have resulted in sulfate being present in the inside of the liposome, as of Barenholz, page 121, right column, reproduced below.
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Use of gradients to load the active agent would appear to result in high levels of loading, as of Barenholz, page 121, section 2.3.3., paragraph bridging left and right columns.
Barenholz differs from the claimed invention because, while Barenholz teaches an anion (sulfate), Barenholz does not teach an anionic lipid. In contrast, the lipids taught by Barenholz are neutral, including zwitterionic lipids.
For the purposes of this rejection, the examiner takes the position that Barenholz and Szoka are deficient because neither reference is understood to enable successful gradient loading of anionic liposomes.
Hayes et al. (hereafter referred to as Hayes) is drawn to liposomes loaded with chelating agents. Hayes teaches the following, as of page 19, Example 30, relevant text reproduced below.
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The above-reproduced text appears to show remote gradient loading of the cationic active agent DFP (which is an abbreviation for deferoxamine) using an anionic liposome, wherein said anionic liposome comprises phosphatidylcholine (a zwitterionic lipid with an overall neutral charge), DOPG (an anionic lipid), and cholesterol, as of the above-reproduced paragraph. Hayes teaches other examples of anionic liposomes being successfully loaded via gradient loading, such as the liposome comprising POPC/Chol/DSPG as of page 14, Example 7, paragraphs 0137-0138.
It would have been prima facie obvious for one of ordinary skill in the art to have loaded the liposome of Szoka via gradient loading. Barenholz teaches gradient loading of a doxorubicin containing liposome, and teaches that this method of loading results in high levels of incorporation of active agent, as of Barenholz, page 121, section 2.3.3. As such, the skilled artisan would have been motivated to have modified the liposome of Szoka to have loaded active agent via gradient to have predictably improved loading levels of active agent with a reasonable expectation of success. The skilled artisan would have had a reasonable expectation of successful gradient loading of an anionic liposome because successful gradient loading of an anionic liposome was achieved by Hayes.
As to claim 1, the claim requires a lipid nanoparticle. The skilled artisan would have understood the liposome of the prior art to have been a lipid nanoparticle. This is because the liposome of the prior art is made of lipids. This is also because the liposome of the prior art is sized about 100 nm, as of Barenholz, page 120, left column, top paragraph, which is sufficiently small to be a nanoparticle.
As to claim 1, the claim requires a neutral lipid. The phosphatidylcholine and cholesterol of Szoka and the PEGylated lipid of Barenholz are understood to read on this requirement.
As to claim 1, the claim requires an anionic lipid. The egg phosphatidylglycerol of Szoka is understood to read on this requirement.
As to claim 1, the claim requires an active pharmaceutical agent having a positive charge. The doxorubicin of Szoka and Barenholz, as well as the cis-platinum of Szoka are understood to read on this requirement. Both of these active agents have amine groups which become protonated at neutral pH, resulting in a positive charge.
As to claim 1, the claim requires an ion that is anionic. The sulfate of Barenholz is understood to read on this requirement.
As to claim 1, the claim recites that there is a complex formed of anionic lipid, (cationic) active agent, and anion. While neither Szoka nor Barenholz specifically teach this, the skilled artisan would have been aware that opposite charges attract one another. As such, the skilled artisan would have expected that the cationic charge of the active agent (e.g. doxorubicin and/or cisplatin) would have engaged in ionic bonding with the egg phosphatidylglycerol of Szoka and the sulfate or Barenholz, resulting in the formation of the recited complex. The discovery of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer. See MPEP 2112(I).
As to claim 1, the claim requires that the outer lipid monolayer comprises neutral lipids. The examiner notes that both Szoka and Barenholz teach a lipid bilayer rather than a monolayer. Nevertheless, as best understood by the examiner, the recited outer lipid monolayer refers to the outer layer of the lipid bilayer; see the section of the office action above entitled “Claim Interpretation.” The skilled artisan would have expected that the phosphatidylcholine and cholesterol of Szoka as well as the PEG-lipid of Barenholz would have been found in this layer. In support of this, the examiner notes at least Barenholz, page 124, right column, figure 3, reproduced below, which shows the PEG-lipid in the outer layer.
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As such, the skilled artisan would have expected that the neutral lipids in the prior art would have been in the outer layer of the lipid bilayer.
As to claim 4, Szoka appears to teach 6 moles of cholesterol to 16 moles of total lipid as of Example 2 of Szoka. It is unclear if this would have resulted in an amount of cholesterol within the claimed range. Nevertheless, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. See MPEP 2144.05(II)(A). In this case, the general conditions of a lipid nanoparticle comprising both cholesterol and other lipids has been taught by the prior art. As such, it would not have been inventive for the skilled artisan to have discovered the optimum or workable ranges of cholesterol via routine experimentation.
As to claim 5, Szoka teaches a phosphatidylglycerol, which is an anionic lipid, to phosphatidylcholine molar ratio of 7 to 3. It is unclear if this would have resulted in a ratio within the claimed range. Nevertheless, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. See MPEP 2144.05(II)(A). In this case, the general conditions of a lipid nanoparticle comprising both anionic lipids and phosphatidylcholine has been taught by the prior art. As such, it would not have been inventive for the skilled artisan to have discovered the optimum or workable ranges of anionic lipids and neutral lipids via routine experimentation.
As to claim 6, Szoka teaches egg phosphatidylglycerol as of Example 2, as explained above. Szoka also teaches hydrogenated soy phosphatidylcholine, as of Szoka, at least column 6, line 18.
As to claim 7, Szoka teaches doxorubicin, as of Szoka, Example 2. Barenholz also teaches doxorubicin, as of the title and abstract of Barenholz.
As to claim 8, while the prior art does not appear to explicitly teach a drug to lipid ratio, Barenholz provides extensive teachings about how drug to lipid ratio can be optimized via gradient loading, as of the entirety of page 122 of Barenholz. As such, the skilled artisan would have been motivated to have optimized the loading level of active agent to have been within the claimed range. The skilled artisan would have been motivated to have optimized a result-effective variable. See MPEP 2144.05(II)(B). In this case, the extensive teachings about how drug loading can be modified in a gradient loaded liposome in page 122 of Barenholz would appear to show that drug loading is a result-effective variable.
As to claim 9, this claim is drawn to the normalized release. Barenholz provides extensive teachings about how to measure and modify release rate, as of pages 123-124, section 2.4. As such, in view of these teachings, the skilled artisan would have been motivated to have optimized and/or modified the release rate to have been in the claimed range. The skilled artisan would have been motivated to have optimized a result-effective variable. See MPEP 2144.05(II)(B). In this case, the extensive teachings about how release rate can be modified in a gradient loaded liposome in page 124 of Barenholz would appear to show that release rate is a result-effective variable.
As to claim 12, Szoka teaches cis-platinum as of column 14, Example 4. This is understood to read on the required cisplatin.
As to claim 13, the rationale applied by the examiner above in regard to the drug to lipid ratio in claim 8 is also applicable to claim 13.
As to claim 14, as best understood by the examiner, the lipids in the prior art were mixed. The prior art appears to be silent as to whether this mixing is rapid. Nevertheless, product-by-process claims are not limited to the manipulations of the recited steps, only to the structure implied by the steps. See MPEP 2113(I). Once the examiner provides a rationale tending to show that the claimed product appears to be the same or similar to that of the prior art, although produced by a different process, the burden shifts to applicant to come forward with evidence establishing a nonobvious difference between the claimed product and the prior art product. See MPEP 2113(II). In this case, the claimed invention is similar to that of the prior art for the reasons set forth above in regard to claim 1. As such, the burden shifts to applicant to establish a non-obvious difference between the claimed invention and prior art.
As to claim 15, the product-by-process rationale applied to the examiner regarding claim 14 also applies to claim 15.
As to claim 16, none of Szoka or Barenholz appear to teach a nucleic acid.
As to claim 17, the sulfate of Barenholz is understood to read on the required bivalent ion.
As to claim 37, the compositions of Szoka and Barenholz are meant to be injected into a subject as they deliver a drug to be used by the subject. See Szoka, column 5, lines 60-68. The skilled artisan would have been motivated to have optimized the administered dosage in order to have predictably increased therapeutic effect while minimizing side effects with a reasonable expectation of success.
Claim(s) 2-3 and 18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Szoka Jr. et al. (US Patent 5,077,057) in view of Barenholz (Journal of Controlled Release 160 (2012), page 117-134) and Hayes et al. (US 2017/0239182 A1), the combination further in view of Bonechi et al. (Biophysical Chemistry, Vol. 233, 2018, pages 55-63).
Szoka is drawn to a liposome which may comprise various active agents including but not limited to doxorubicin. Barenholz is drawn to doxorubicin liposomes loaded with sulfate anion. Hayes teaches successful gradient loading of an anionic liposome. See the rejection above over Szoka in view of Barenholz and Hayes by themselves. Szoka teaches an anionic liposome comprising egg phosphatidylglycerol and other lipids.
None of the above references teach a lipid particle comprising dioleoyl phosphatidic acid (DOPA) and dioleoyl phosphatidylethanolamine (DOPE).
Bonechi et al. (hereafter referred to as Bonechi) is drawn to a liposome comprising quercetin and rutin, as of Bonechi, page 55, title and abstract. In one embodiment, Bonechi teaches a liposome comprising DOPE and DOPA (i.e. dioleoyl phosphatidic acid), as of Bonechi, page 56, right column, section 2.2, relevant text reproduced below.
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This liposome appears to be able to administer and deliver active agent.
Bonechi does not teach an ion (that is other than the active agent and anionic lipid) that forms a complex with the active agent.
It would have been prima facie obvious for one of ordinary skill in the art to have substituted the lipid mixture of Bonechi in place of that of Szoka in order to have delivered the active agents of Szoka and/or Barenholz. Szoka is drawn to an anionic liposome comprising anionic lipids and neutral lipids. Bonechi is also drawn to an anionic liposome with anionic lipids and neutral lipids that differ from those of Szoka. As such, the skilled artisan would have been motivated to have substituted the lipids of Bonechi in place of those of Szoka in order to have predictably administered the active agents of Szoka and Barenholz with a reasonable expectation of success. The simple substitution of one known element (e.g. the DOPA/DOPE of Bonechi) in place of another (e.g. the EPG/EPC/Cholesterol of Szoka) in order to achieve predictable results (delivery of an active agent) is prima facie obvious. See MPEP 2143, Exemplary Rationale B.
As to claim 2, Bonechi teaches both DOPA and DOPE.
As to claim 3, Bonechi appears to teach a 1:1 ratio of DOPA and DOPE. This differs from the claimed ratio. Nevertheless, generally, differences in concentration (or in this case, ratio of DOPA and DOPE concentration) between the claimed invention and prior art will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. See MPEP 2144.05(II)(A). In this case, no evidence of criticality appears to have been presented. Additionally, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. See MPEP 2144.05(II)(A). In this case, the general conditions of a DOPA/DOPE liposome have been taught by the prior art. As such, it would not have been inventive for the skilled artisan to have discovered the optimum or workable range of DOPA/DOPE ratio via routine experimentation.
As to claim 18, the examiner notes that Szoka teaches phosphatidylglycerol lipids. Nevertheless, the skilled artisan would have been motivated to have substituted DOPA, as of Bonechi, in place of the phosphatidylglycerol of Szoka as both are anionic lipids, for the reasons explained above. The resultant composition would not have included phosphatidylglycerol.
Claim(s) 10-11 is/are rejected under 35 U.S.C. 103 as being unpatentable over Szoka Jr. et al. (US Patent 5,077,057) in view of Barenholz (Journal of Controlled Release 160 (2012), page 117-134) and Hayes et al. (US 2017/0239182 A1), the combination further in view of Heath et al. (US 2014/0079773 A1).
Szoka is drawn to a liposome which may comprise various active agents including but not limited to doxorubicin. Barenholz is drawn to doxorubicin liposomes loaded with sulfate anion. Hayes teaches successful gradient loading of an anionic liposome. See the rejection above over Szoka in view of Barenholz and Hayes by themselves. Szoka teaches a variety of active agents as of e.g. claim 14 of Szoka. Barenholz, while drawn to doxorubicin liposomes, teaches loading of weak acids and weak bases generically as of Barenholz, page 121, left column, top paragraph.
None of the above references teach doxycycline.
Heath et al. (hereafter referred to as Heath) is drawn to liposomes, as of Heath, title and abstract. Heath teaches encapsulation of doxycycline, as of page 11, Example 3, paragraph 0125. Heath appears to teach that doxycycline is encapsulated via gradient in paragraph 0125.
Heath differs from the claimed invention because Heath does not teach an anionic lipid.
It would have been prima facie obvious for one of ordinary skill in the art to have used the liposome of Szoka in view of Barenholz to have delivered doxycycline. Szoka is drawn to a liposome to deliver a wide range of active ingredients, and Barenholz teaches that the gradient loading used for doxorubicin can be used for a variety of active ingredients having the required weak base or weak acid moiety. Heath teaches that doxycycline can be loaded into a liposome via a gradient. As such, the skilled artisan would have been motivated to have loaded doxycycline into the liposome of Szoka in view of Barenholz for predictable delivery of doxycycline with a reasonable expectation of success.
As to claim 10, the doxycycline of Heath is understood to read on the limitation of this claim.
As to claim 11, while the prior art does not appear to explicitly teach a drug to lipid ratio, Barenholz provides extensive teachings about how drug to lipid ratio can be optimized via gradient loading, as of the entirety of page 122 of Barenholz. As such, the skilled artisan would have been motivated to have optimized the loading level of active agent to have been within the claimed range. The skilled artisan would have been motivated to have optimized a result-effective variable. See MPEP 2144.05(II)(B). In this case, the extensive teachings about how drug loading can be modified in a gradient loaded liposome in page 122 of Barenholz would appear to show that drug loading is a result-effective variable.
Response to Arguments Regarding Obviousness Rejection
Applicant has presented arguments regarding the previously applied obviousness rejection, as of applicant’s response on 29 August 2025 (hereafter referred to as applicant’s response). These arguments are addressed below.
Applicant has presented the following argument, as of page 8, second paragraph of applicant’s response.
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This is not persuasive. As best understood by the examiner, remote gradient loading of liposomes has been achieved for anionic liposomes, as of Hayes et al. (US 2017/0239182 A1), which is addressed above. This appears to be sufficient to rebut the general conclusion of the scientific points made by the above-reproduced paragraph. As best understood by the examiner, the main point of the above-reproduced argument is that gradient loading of an anionic liposome cannot be successful because of the scientific reasons presented in the above-reproduced paragraph. However, this does not appear to be correct in view of the successful gradient loading of a liposome taught by Hayes.
Applicant makes the following arguments on page 8, last full paragraph, relevant text reproduced below.
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The examiner does not dispute that ammonium sulfate “breaks down” into ammonium ions and sulfate ions, though the examiner does take the position that the term “dissociates” is generally used in the art in place of “breaks down.” However, the examiner does make the following comments. First, at neutral pH, the proportion of ammonium ions that further break down into ammonia is very few; likely close to 1 in 100-1000 break down in this manner. This is because the pKa of ammonium, which is the pH at which the protonated ammonium conjugate acid and the deprotonated conjugate base are equally represented, is in the 9-11 range and is therefore multiple pH units above the neutral pH. When the pH is lower than the pKa, the conjugate acid form predominates; in this case, the conjugate acid is ammonium ion. As such, at neutral pH, the ammonium ion predominates over ammonia.
The examiner also takes the position that the term “hydrogen ion”, while used frequently in general chemistry texts, is not actually the most correct description of the species formed by ammonium ion interconverting into ammonia. In contrast, the species formed is most likely protonated water, otherwise known as hydronium ion. This can be represented as H3O+, though other hydronium ion species likely exist.
Applicant makes the following argument, as of pages 8-9, relevant text reproduced below.
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This is not persuasive. Hayes teaches successful remote gradient loading of an anionic liposome. As such, applicant’s arguments that remote gradient loading of an anionic liposome would not have been successful is not persuasive. Obviousness requires a reasonable expectation of success, not absolute predictability. See MPEP 2143.02.
Applicant goes on to provide a scientific explanation as to why the skilled artisan would have expected remote gradient loading of anionic liposomes to have failed, as of page 9 and the top paragraph of page 10. This argument is not persuasive because Hayes appears to have taught successful remote gradient loading of anionic liposomes. Additionally, the scientific arguments presented by applicant are not understood to be evidence that the skilled artisan would have expected remote gradient loading to have failed. Arguments presented by applicant cannot take the place of evidence in the record. See MPEP 2145(I) and 716.01(c)(II).
Applicant then makes the following argument, as of page 10, relevant text reproduced below.
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Similar arguments are made regarding the allegedly critical complexation sequence on page 11, second paragraph. This is not persuasive regarding the claimed invention. Applicant’s arguments regarding the specific complexation sequence may be commensurate in scope with claims drawn to the method of making a composition. However, the elected claims are drawn to a composition itself. As such, applicant’s arguments are not persuasive with respect to the elected claims.
Applicant then cites various case law on page 11, relevant text reproduced below.
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The case of In re Omeprazole Patent Litigation, 536 F.3d 1361, 87 USPQ2d 1865 (Fed. Cir. 2008) is discussed in MPEP 2143(I)(A), Example 3, wherein the examiner has reproduced relevant text below.
The case of In re Omeprazole Patent Litigation, 536 F.3d 1361, 87 USPQ2d 1865 (Fed. Cir. 2008), is one in which the claims in question were found to be nonobvious in the context of an argument to combine prior art elements. The invention involved applying enteric coatings to a drug in pill form for the purpose of ensuring that the drug did not disintegrate before reaching its intended site of action. The drug at issue was omeprazole, the generic name for gastric acid inhibitor marketed as Prilosec®. The claimed formulation included two layers of coatings over the active ingredient. …
The Federal Circuit affirmed the district court’s decision that the claimed invention was not obvious. Even though subcoatings for enteric drug formulation were known, and there was no evidence of undue technical hurdles or lack of a reasonable expectation of success, the formulation was nevertheless not obvious because the flaws in the prior art formulation that had prompted the modification had not been recognized. Thus there would have been no reason to modify the initial formulation, even though the modification could have been done. Moreover, a person of ordinary skill in the art likely would have chosen a different modification even if they had recognized the problem.
Office personnel should note that in this case the modification of the prior art that had been presented as an argument for obviousness was an extra process step that added an additional component to a known, successfully marketed formulation. The proposed modification thus amounted to extra work and greater expense for no apparent reason. …
As such, In re Omeprazole Patent Litigation, 536 F.3d 1361, 87 USPQ2d 1865 (Fed. Cir. 2008) appears to relate to a situation wherein applicant did what appeared to be extra work and/or greater expense for no apparent reason; however by doing so, solved a problem that the prior art did not recognize, resulting in a determination of non-obviousness. It is unclear how this relates to the fact pattern of the instant case. This is because applicant did not appear to argue that the claimed invention includes extra work for what would have appeared to be no apparent reason based upon the teachings of the prior art. As such, the fact pattern of In re Omeprazole Patent Litigation, 536 F.3d 1361, 87 USPQ2d 1865 (Fed. Cir. 2008) as explained by the MPEP appears to be significantly different from the fact pattern of the instant application.
Regarding Crocs, Inc. v. U.S. Int'l Trade Comm'n, 598 F.3d 1294, 93 USPQ 1777 (Fed. Cir. 2010), this case is discussed as of MPEP 2143(I)(A), Example 4. Relevant text is reproduced from the MPEP below.
The Federal Circuit continued, stating that even if – contrary to fact – the claimed invention had been a combination of elements that were known in the prior art, the claims still would have been nonobvious. There was testimony in the record that the loose fit of the heel strap made the shoe more comfortable for the wearer than prior art shoes in which the heel strap was constantly in contact with the wearer’s foot. In the claimed footwear, the foam heel strap contacted the wearer’s foot only when needed to help reposition the foot properly in the shoe, thus reducing wearer discomfort that could arise from constant contact. This desirable feature was a result of the friction between the base section and the strap that kept the strap in place behind the Achilles portion of the wearer’s foot. The Federal Circuit pointed out that this combination "yielded more than predictable results." Id. at 1310, 93 USPQ2d at 1788. Aguerre had taught that friction between the base section and the strap was a problem rather than an advantage, and had suggested the use of nylon washers to reduce friction. Thus the Federal Circuit stated that even if all elements of the claimed invention had been taught by the prior art, the claims would not have been obvious because the combination yielded more than predictable results.
The relevance of this to the fact pattern of the instant case is not clear to the examiner. First, the subject matter of footwear in the cited case is unrelated to the subject matter of the instantly claimed invention. Secondly, the general idea that the combination yielded more than predictable results is not persuasive in view of the teachings of Hayes, which would appear to teach that remote gradient loading of anionic liposomes is predictable.
Applicant then argues that Barenholz teaches away from anionic liposomes; this argument was presented starting on the last four lines of page 11 through page 13 of applicant’s response. Applicant’s argument is that the presence of a negative charge would have resulted in undesirable uptake of the liposome by the reticuloendothelial system after administration.
The examiner previously addressed this issue in the prior office action mailed on 29 April 2025.
This is not persuasive. Even if, purely en arguendo, the OLV-DOX discussed in Barenholz is considered to be a failure, it is not clear that the reason that OLV-DOX failed because it is anionic. The examiner presents the following argument in support of this position.
First, it appears that at least one reason for failure of OLV-DOX relates to its increase uptake by the reticuloendothelial system (which is frequently abbreviated as “RES”), which causes the doxorubicin to be removed from the bloodstream. In support of this position, the examiner cites Barenholz, page 118, third paragraph, relevant text reproduced below.
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As such, Barenholz indicates that OLV-DOX underwent significant uptake by the reticuloendothelial system.
Secondly, Barenholz teaches that OLV-DOX comprises phosphatidylcholine, phosphatidylglycerol, and cholesterol, as of Barenholz, page 118, left column, top paragraph. Notably absent in that formulation is a PEGylated lipid. Barenholz teaches that the inclusion of PEGylated lipids improves plasma circulation time by avoidance of uptake by the reticuloendothelial system. See Barenholz, page 124, section 2.5. This paragraph of Barenholz indicates that the inclusion of steric stabilizers reduce liposome uptake by the reticuloendothelial system (abbreviated “RES”) and that PEG-lipids are steric stabilizers and therefore reduce liposome uptake by the reticuloendothelial system.
Therefore, as best understood by the examiner, the use of PEGylated lipids or other steric stabilizers in liposomes may not have been standard at the time OLV-DOX was formulated, but became a standard component of liposomes as of the time of the publication of the Barenholz reference, let alone as of the effective filing date of the instant application.
As such, the skilled artisan would have been unable to conclude from the teachings of Barenholz that the failure of OLV-DOX to avoid the reticuloendothlial system was due the anionic charge of the OLV-DOX liposomes rather than due to the lack of PEGylated lipids or other steric stabilizers in OLV-DOX.
In response to this position, applicant makes the following arguments on page 13 of applicant’s response.
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This is not persuasive. A comparison of OLV-DOX, which is unpegylated anionic liposome comprising doxorubicin, to Doxil, which is a well-known trade name referring to a pegylated, neutral liposome comprising doxorubicin, is not a fair comparison. This is because the skilled artisan would have been aware that PEG helps mitigate reticuloendothelial system uptake. In order to show that the prior art teaches away from the use of anionic liposome, applicant would have to point to a prior art comparison of pegylated anionic liposome against pegylated neutral liposome, because the liposome is pegylated in both cases. As this has not been taught by Barenholz, applicant’s argument that Barenholz teaches away from using an anionic liposome is not persuasive.
Applicant then cites In re Ratti, 270 F.2d 810, 813, 123 USPQ 349, 352 (CCPA 1959), as of page 14 of applicant’s response. This case has been discussed in the MPEP, as of MPEP 2143.01(VI), and relevant text related to this reference has been reproduced below.
If the proposed modification or combination of the prior art would change the principle of operation of the prior art invention being modified, then the teachings of the references are not sufficient to render the claims prima facie obvious. In re Ratti, 270 F.2d 810, 813, 123 USPQ 349, 352 (CCPA 1959) (Claims were directed to an oil seal comprising a bore engaging portion with outwardly biased resilient spring fingers inserted in a resilient sealing member. The primary reference relied upon in a rejection based on a combination of references disclosed an oil seal wherein the bore engaging portion was reinforced by a cylindrical sheet metal casing. The seal construction taught in the primary reference required rigidity for operation, whereas the seal in the claimed invention required resiliency. The court reversed the rejection holding the "suggested combination of references would require a substantial reconstruction and redesign of the elements shown in [the primary reference] as well as a change in the basic principle under which the [primary reference] construction was designed to operate.").
This is not persuasive. In the cited case, there appears to be a tradeoff between rigidity and resiliency. The prior art in the cited case appeared to favor rigidity, whereas the invention of the cited case appeared to favor resiliency, thereby resulting in the prior art operating by a different principle than the invention in the cited case. However, there does not appear to be a similar tradeoff in the instant case. As such, the subject matter of In re Ratti, 270 F.2d 810, 813, 123 USPQ 349, 352 (CCPA 1959) appears unrelated to the subject matter of the instant invention.
Applicant then makes the following argument, as of page 15, top paragraph.
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This is not persuasive. As best understood by the examiner, the pKa of aliphatic amines is generally in the 9-11 range. As such, the skilled artisan would have expected that aliphatic amines would have been mostly protonated and positively charged at pH values below the pKa.
The examiner does note that none of the cited references appear to explicitly teach the pH of the aqueous interior. Nevertheless, Szoka does appear to teach making liposomes with the pH buffered at 7.4, as of Szoka, column 11, Table 1, reproduced below.
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As such, there is no indication that the pH of the aqueous interior would have been strongly basic. As such, there would have been a reasonable expectation that the pH of the aqueous interior would have been neutral; and in that case, there would have been a reasonable expectation that there would have been sufficient protons to protonate amine groups in the active agent. This would especially have been the case in the presence of a pH buffer, such as Hepes, as of the above table.
Applicant has then made the following argument on pages 15-16, relevant paragraphs reproduced below.
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This is not persuasive. This is because the idea that the term “normalized release”, as used in the instant application, implies a comparison of the claimed invention to the doxorubicin liposome known by the trade name “Doxil” does not appear to have been supported by the original application as filed. In contrast, the phrase “normalized release” appears to have been defined in the following manner, as of page 4, bottom paragraph of the instant specification, which has been reproduced below.
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Nothing in the above-reproduced text indicates that the phrase “normalized release” refers to a comparison against Doxil.
Applicant also cited figures 9A and 9B, as of applicant’s response, page 16. The examiner has reproduced these figures below.
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The above-reproduced results would appear to show that the formulation referred to as LNP-1 provides better results regarding killing cancer cells and keeping laboratory animals with cancer alive as compared with Doxil.
Nevertheless, the following issues remain unclear to the examiner. It is unclear as to what formulation actually constitutes the LNP-1 tested in the above-reproduced figure. Looking to the specification on page 5, last paragraph, it appears that the phrase “LNP-1 can refer to multiple different liposomes made from multiple different types of lipids. Relevant text from this paragraph that appears to support this position has been reproduced below.
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The above-reproduced text would appear to indicate that the phrase “LNP 1” can refer to multiple liposomes with multiple different types of lipids. As such, in view of this, it is unclear as to exactly what was tested in figures 9A and 9B. Therefore, the data presented in figures 9A and 9B does not appear to be probative of non-obviousness at this time.
Terminal Disclaimer
The terminal disclaimer filed on 29 August 2025 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of US application serial number 17/697,941 has been reviewed and is accepted. The terminal disclaimer has been recorded.
Note Regarding Email Communication
Applicant made the following statement on page 17 of applicant’s response.
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The examiner notes the following in regard to the use of email communications in the patent examination process, as per MPEP 502.03.
Without a written authorization by applicant in place, the USPTO will not respond via email to any Internet correspondence which contains information subject to the confidentiality requirement as set forth in 35 U.S.C. 122….USPTO employees are NOT permitted to initiate communications with applicants via email unless there is a written authorization of record in the patent application by the applicant.
The examiner further takes the position that the above-reproduced statement does not constitute a written authorization for the use of email because it is not on a separate piece of paper. In support of this position, the examiner cites the following text from MPEP 502.03, which is reproduced below with emphasis on one particular word by the examiner.
To facilitate processing of the internet communication authorization or withdrawal of authorization, the Office strongly encourages use of Form PTO/SB/439, available at www.uspto.gov/PatentForms. The form may be filed via the USPTO patent electronic filing system using the document description Internet Communications Authorized or Internet Communications Authorization Withdrawn to facilitate processing. The internet authorization must be submitted on a separate paper to be entitled to acceptance in accordance with 37 CFR 1.4(c). The separate paper will facilitate processing and avoid confusion.
It is the examiner’s understanding from the above-reproduced text from the MPEP that (a) the internet communication authorization must be on a separate piece of paper, and (b) use of the PTO/SB/439 form is strongly encouraged.
As the text on page 17 of applicant’s response is not on a separate piece of paper, it is not considered a valid Internet Communication Authorization. Therefore, as of the mailing of this office action, the examiner takes the position that the examiner is not authorized to initiate email communication with representative of applicant related to this application.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ISAAC SHOMER whose telephone number is (571)270-7671. The examiner can normally be reached 7:30 AM to 5:00 PM Monday Through Friday.
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ISAAC . SHOMER
Primary Examiner
Art Unit 1612
/ISAAC SHOMER/ Primary Examiner, Art Unit 1612